Method for preparing alkyl acyloxy acrylates



Patented Jan. 11, 1949 Robert D, Babsqlb Bahway; 9., assignor td Merck & C0.,\Inc., Bahway, ll J a corporation of New Jersey",

No Drawing, dpplicationJuly12,1946, Serial No. 683,143 .2

; This invention is concerned generally with novel chemical processes; more particularly it relates to an improvedmethod for the manufacture of esters a-halo-,8,B-dialkoxy-propionic acid, useful in the preparation of u-formyl-phenaceturamide, a pri-' mary intermediate in the synthesis of penicillin.

It isnow discovered, in accordance'with the present invention, that -a-ha1o-fl,c-dialkoxy proplonic esters can be synthesized by reactions indicated as follows:

Hydrocarb on M.OCH==CHCOOR (3) Acylating agent wherein R is alkyl, M is an alkali metal, and X is halogen.

The reactions indicated above are conducted as follows: An alkyl acetate (1) is reacted with an alkyl formate (2) and an alkali metal to produce the corresponding alkyl a-(metallo-formyl) acetate (3) this compound is reacted wtih an acylating agent derived from an aliphatic carboxylic acid to produce the corresponding alkyl fi-acyloxy-acrylate (4) said alkyl p-acyloxy acrylate is then reacted with a halogen and an aliphatic alcohol to produce the corresponding alkyl m-halop,s-dialkoxy-propionate (5). Compounds of this class can be converted to esters of u-phenacet amido-p,p-dialkoxy-propionate as follows: The alkyl a-halo-p,p-dialkoxy-propionate is hydrolyzed and the resulting a-halo-B, 8-dialkoxy-propicnic acid is heated with aqueous ammonia, whereby the a-halo substituent is converted to an wamino group; the a-amino-fi,fl-dialkoxy propionic acid is then reacted with a phenacyl halide and the product esterified to produce the desired ester of I a-phenacetamido-fl,B-dialkoxy propionate. These reactions are described in detail in co-pending applications, Serial No. 728,724, filed February 14, 1947, and Serial No. 710,945, filed November 19, 1946. For example methyl acetate can be condensed with methyl formate and sodium to form methyl a-(sodioformyl) -acetate; this can then be treated with acetyl chloride to produce methyl fi-acetoxy-acrylate. When this compound is reacted with chlorine and methyl alcohol, and

2 l in copending application, Serial No. 636,516, filed December 21, 1945. A

Prior art methods showing the reaction of ozsodioforrnyl) -acetate with acetyl chloride are known butin these processes,the reaction mixture is dis tilled directly, which procedure results inlconsideifable decomposition and polymerization of the product andthe resulting yield of ethyl ,c-acetoxy-acrylate is limited to approximately 22% of theory. ,No processis disclosed in the prior art for converting alkyl B-acyloxy-acrylates to alkyl u-halo-p,p-dialkoxy propionates.

It is now discovered, according to the present invention, that an alkyl a-(metallo-formyl) acetate can be reacted with an aliphatic acyl halide and the reaction product neutralized to a pH of approximately 6-7 and then distilled, whereby the corresponding alkyl p-acyloxy acrylate is obtained in yields of nearly 60% of theory. It is further discovered that these alkyl p-acyloxy acrylates can be reacted with a halogen and an aliphatic alcohol to produce the desired alkyl a-halo-p,p-dialkoxy propionates in yields of over 80% of theory.

In carrying out the reaction, the alkyl or- (metallo-formyl) -'acetate is reacted with an aliphatic acyl halide such as acetyl chloride, propionyl bromide, butyryl chloride and the like, in dialkyl ether solution. The time for the reaction varies, depending upon the reactants and the temperature employed, from approximately hour to several hours. It is presently preferred to employ temperatures of approximately 35 (3.; at

this temperature, the reaction in the case of ethyl a-(sodio-formyD-acetate and acetyl chloride is substantially complete in approximately hour. The reaction mixture is neutralized to a pH of approximately 7, for example, by shaking with an aqueous solution containing a mild alkaline agent such as sodium bicarbonate or potassium bicarbonate. The ether layer is separated, washed with water, and ether evaporated and the residual oil distilled, preferably under reduced pressure to produce the alkyl p-acyloxy aorylate.

The'following example illustrates a method of carrying out the present invention, but it is to be understood that this example is given by way of illustration and not of limitation.

Example A mixture of about 155 g. of ethyl a-sodioformyl acetate and about 700 cc. of anhydrous ether is cooled to approximately -10 0. About 80.2 cc. of acetyl chloride is added to this mixture with stirring over approximately a 5 min- The residue isdistilled under reduced pressure to produce approximately 106 g. of ethyl 5-aceto1ry-aorylate; B. P. 94-97" C. at 18 mm.; n =1-.4459 yield approximately 60% of theory based on ethyl sodio-formyl acetate.

Modifications may be made in carryingout they present invention without departing from. the

spirit and scope thereof and it is to be understood that the invention. is to be limited only by the appended claims.

l. The process which comprises'reacting; in dialkyl ether solution. an alkyl a-metaiio-formylacetate with a lower aliphatic carboxylic" acid halide'directly' neutralizing the reaction mixture to a pH of approximately '7 and recovering the corresponding alkyl fi acyloxy-acrylate fromsaid neutralized reaction mixture.

2: The process which comprlsesreaeting; in-

diethyl ethersolution, ethyl a-sodio-formyl' acetate with acetyl chloride, directly neutralizing the reaction mixture to a pH of approximately 7 with aqueous sodium bicarbonate solution and recovering ethyl ,B-acetoxy acrylate from said neutralized reaction mixture.

' ROBERT D. BABSON.

REFERENCES CITED The-following references are of record in the file ofthis" patent:

UNITED STATES PATENTS Number Name Date 2390,1335 Sobotka et a1. Dec. 4, 1945 2,394.255 Northey Feb. 5, 1946 2,405,820 Faith Aug. 13, 1946 OTHER REFERENCES Pechmann: Ber. Deut. Chem. Ges., vol. 25 (1892) pages 1047-1051.

Wislicenus et ah? LiebigsAnnalen-fi vol. 316 (1901), pages 18; 26', 27, 37 and 39.

Wislicenus: "Ber; Deut'. Chem.,vo1. 43 (1910), page 3531.

S-ugasawa, Chem; Zen't., (1927), part II, page Oroshnik et al.: Journal American Chemical Society? vol. 67 (May 1945), pages 722-723.

Merck Report, 12d, February'18, 1944 (Sept. 27, 1945) page 5. 

